SUN-13837

To avoid production of a phospholipidosis-inducing metabolite, we replaced the amide structure of SUN13837 (1) with a 1,2,3-triazole. The resulting 1,2,3-triazole analog of 1 (compound 2) displayed greater neuroprotective activity than 1. Structural modification of 2 yielded compound 10, which showed improved neuroprotective activity and negligible mechanism-based inactivation against CYP3A4. In addition, installation of a methyl group at the 5-position of 1,2,3-triazole of 10 significantly boosted the neuroprotective activity. These 1,2,3-triazole derivatives displayed reduced phospholipidosis risk, sufficient systemic exposure, and high central nervous system penetration, and therefore may be potentially useful agents for the treatment of neurodegenerative diseases.

Our understanding of the pathophysiological processes that comprise the early secondary phases of spinal cord injury such as spinal cord ischemia, cellular excitotoxicity, ionic dysregulation, and free-radical mediated peroxidation is far greater now than ever before, thanks to substantial laboratory research efforts. These discoveries are now being translated into the clinical realm and have led to targeted upfront medical management with a focus on tissue oxygenation and perfusion and include avoidance of hypotension, induction of hypertension, early transfer to specialized centers, and close monitoring in a critical care setting. There is also active exploration of neuroprotective and neuroregenerative agents; a number of which are currently in late stage clinical trials including minocycline, riluzole, AC-105, SUN13837, and Cethrin. Furthermore, new data have emerged demonstrating that the timing of spinal cord decompression after injury impacts recovery and that early decompression leads to significant improvements in neurological recovery. With this review we aim to provide a concise, clinically relevant and up-to-date summary of the topic of acute spinal cord injury, highlighting recent advancements and areas where further study is needed.